Over two million children are born to HIV-infected women annually. With advances in access to antiretroviral therapy and strategies to prevent mother-to-child transmission (MTCT), infant infection has become uncommon in settings like Botswana. However, these HIV-exposed but uninfected infants remain at 2 to 4-fold greater risk of dying than matched HIV-unexposed children, accounting for more than half of all deaths before age 5 in Botswana. Despite its great public health importance, the etiology of this mortality gap is unknown and strategies to mitigate this excess mortality in HIV-exposed uninfected (HIV-EU) infants have not been previously studied. Advanced maternal HIV disease is associated with decreased transfer of protective antibodies and poor infant outcomes. Treatment of maternal HIV, through expanded use of maternal highly- active antiretroviral therapy (HAART) for prevention of MTCT, as endorsed by recently revised WHO guidelines, may also improve health outcomes of uninfected infants. However, maternal HAART is associated with increased risk of prematurity, low birth weight, and severe infant anemia- all important predictors of increased mortality. Utilizing unique clinical data and specimens from well-characterized cohorts at the Botswana Harvard AIDS Institute Partnership, the project will examine the critical question of the effect of maternal HAART and other factors on the overall health of HIV-EU infants. The project as two specific aims: 1) determine factors associated with death or hospitalization (including HAART) among 2621 HIV-EU infants in Botswana by pooling data from 4 large cohorts, and 2) determine if reduced infant antibody levels to common pathogens are associated with lack of maternal HAART, and with death or hospitalization in HIV-EU infants. The results of these studies could impact the use of maternal HAART, vaccination strategy, and other interventions to improve outcomes for the rising number of HIV-exposed, uninfected infants. In addition, these mentored projects are part of a detailed Career Development Plan that will provide the Candidate with the knowledge, skills, and experience to successfully transition to an independent investigator. Public Health Relevance Statement (provided by the applicant): Worldwide two million children are born to women with HIV. Most of these infants will not get HIV, but they are still 2-4 times more likely to die by 2 years of age than infants born to mothers without HIV. This project aims to study reasons why this happens with a goal of developing strategies to prevent these deaths.